Engineering Hybrid Peptides and Ionic Liquid-Peptide Conjugates for a Fast Action on Bacterial Membranes

Abstract Fast-acting peptide-based antimicrobials that target bacterial membranes are herein addressed and promise a breakthrough in chronic wound care. Two peptide hybrids (3.1-PP4 and PP4-3.1), engineered by us, resulted from linking PP4 (a non-antimicrobial anti-aging peptide used in cosmetics) to the antimicrobial peptide 3.1. In contrast, the replacement of the latter with an antimicrobial ionic liquid afforded an ionic liquid-peptide conjugate C16-Im-PP4. Herein, we demonstrate their rapid bactericidal action by targeting bacterial membranes via a combination of biophysical assays and microscopy using liposome models of bacterial membranes and live bacteria. Interestingly, the peptide hybrids share a similar membrane-disruptive mechanism against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. In turn, the ionic liquid-peptide conjugate C16-Im-PP4 displayed bacterial-type-dependent behavior. These findings underscore the potential of peptide-based agents to address chronic wounds, which remain vulnerable to infection due to prolonged inflammation and rising antibiotic resistance that is increasingly regarded as a “silent pandemic”.